Enhanced Atherosclerosis in TIPE2-Deficient Mice Is Associated with Increased Macrophage Responses to Oxidized Low-Density Lipoprotein

Abstract

Atherosclerosis has been widely recognized as an inflammatory disease of the arterial wall in which macrophages play a major role. Yet, how macrophage-mediated pathology is regulated during atherosclerosis is poorly understood. TNF-α–induced protein 8–like 2 (TIPE2, also known as TNFAIP8L2) is highly expressed in resting macrophages and can negatively regulate inflammation through inhibiting immune receptor signaling. We report in this article that TIPE2 plays a crucial atheroprotective role likely by regulating macrophage responses to oxidized low-density lipoprotein (ox-LDL). TIPE2-deficient macrophages treated with ox-LDL produced more oxidative stress and proinflammatory cytokines, and exhibited heightened activation of the JNK, NF-κB, and p38 signaling pathways. As a consequence, TIPE2 deficiency in bone marrow–derived cells exacerbated atherosclerosis development in Ldlr−/− mice fed a high-fat diet. Importantly, ox-LDL markedly downregulated TIPE2 mRNA and protein levels in macrophages, suggesting that ox-LDL mediates atherosclerosis by TIPE2 inhibition. These results indicate that TIPE2 is a new inhibitor of atherosclerosis and a potential drug target for treating the disease.

Regulation of inflammation and tumorigenesis by the TIPE family of phospholipid transfer proteins

“…75 In addition, TIPE2 regulates macrophage responses to oxidized low-density lipoproteins (ox-LDL); TIPE2-deficient macrophages produced more oxidative stress and inflammatory cytokines, with associated increases in JNK, NF-κB, and p38 signaling. 76 In conjunction with this finding, TIPE2 deficiency in the bone marrow increased atherosclerosis formation in Ldlr − / − mice fed a high-fat diet, and ox-LDL was found to downregulate TIPE2 mRNA expression. 76 Interestingly, atorvastatin seems to potentiate the LPS-mediated expression of TIPE2, with downstream decreases in inflammatory mediators, including NO synthase and NF-κB.…”

“…76 In conjunction with this finding, TIPE2 deficiency in the bone marrow increased atherosclerosis formation in Ldlr − / − mice fed a high-fat diet, and ox-LDL was found to downregulate TIPE2 mRNA expression. 76 Interestingly, atorvastatin seems to potentiate the LPS-mediated expression of TIPE2, with downstream decreases in inflammatory mediators, including NO synthase and NF-κB. 77 TIPE3 is an oncogenic transfer protein of lipid second messengers TIPE3 is the most recently investigated TIPE family member, and only a few articles have been published regarding this protein.…”

TIPE2 protein prevents injury-induced restenosis in mice

“…TNFAIP8L2 (TIPE2), the tumor necrosis factor (TNF)-α-induced protein 8 (TNFAIP8, TIPE) like 2, is a member of the TNFAIP8 family that plays important roles in controlling inflammation and tumorgenesis by suppressing RAS signaling [7][8][9][10]. Its deficiency in 129/J mice causes fatal inflammatory diseases [8] and abnormal expression in humans is associated with many kinds of diseases, such as hepatocellular carcinoma [7,10], stroke [11], HBV infection [12] and atherosclerosis [13,14]. Our previous studies showed that TIPE2 plays atheroprotective roles by negatively regulating ox-LDL-induced inflammatory responses in macrophages [13,14].…”

“…Its deficiency in 129/J mice causes fatal inflammatory diseases [8] and abnormal expression in humans is associated with many kinds of diseases, such as hepatocellular carcinoma [7,10], stroke [11], HBV infection [12] and atherosclerosis [13,14]. Our previous studies showed that TIPE2 plays atheroprotective roles by negatively regulating ox-LDL-induced inflammatory responses in macrophages [13,14]. Furthermore, TIPE2 could inhibit neointima formation by regulating phenotypic switching of VSMCs during atherogenesis [13,14].…”

“…Our previous studies showed that TIPE2 plays atheroprotective roles by negatively regulating ox-LDL-induced inflammatory responses in macrophages [13,14]. Furthermore, TIPE2 could inhibit neointima formation by regulating phenotypic switching of VSMCs during atherogenesis [13,14]. However, whether TIPE2 plays a role in the vascular remodeling process in response to injury is still unknown.…”